NM_001363.5:c.1255T>A

Variant names:

• chrX-154774701-T-A
• rs1557265435
• NM_001363.5:c.1255T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001363.5(DKC1):​c.1255T>A​(p.Tyr419Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: DKC1 NM_001363.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.60

Genes affected

DKC1 (HGNC:2890): (dyskerin pseudouridine synthase 1) This gene functions in two distinct complexes. It plays an active role in telomerase stabilization and maintenance, as well as recognition of snoRNAs containing H/ACA sequences which provides stability during biogenesis and assembly into H/ACA small nucleolar RNA ribonucleoproteins (snoRNPs). This gene is highly conserved and widely expressed, and may play additional roles in nucleo-cytoplasmic shuttling, DNA damage response, and cell adhesion. Mutations have been associated with X-linked dyskeratosis congenita. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the DKC1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 27 curated benign missense variants. Gene score misZ: 3.3994 (above the threshold of 3.09). GenCC associations: The gene is linked to Hoyeraal-Hreidarsson syndrome, DKC1-related disorder, dyskeratosis congenita, X-linked, dyskeratosis congenita.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897
• PP5: Variant X-154774701-T-A is Pathogenic according to our data. Variant chrX-154774701-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 434943.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKC1	NM_001363.5	c.1255T>A	p.Tyr419Asn	missense_variant	Exon 12 of 15	ENST00000369550.10	NP_001354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKC1	ENST00000369550.10	c.1255T>A	p.Tyr419Asn	missense_variant	Exon 12 of 15	1	NM_001363.5	ENSP00000358563.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dyskeratosis congenita, X-linked Pathogenic:1

Sep 13, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.36	T;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.0	.;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.014	.;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.94	.;P
Vest4		0.83
MutPred		0.30		Loss of phosphorylation at Y419 (P = 0.0059);Loss of phosphorylation at Y419 (P = 0.0059);
MVP		1.0
MPC		2.5
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.69
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1557265435; hg19: chrX-154002976;